bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2025–11–02
nineteen papers selected by
Marco Tigano, Thomas Jefferson University
  1. Structural basis of apoptosis induction by the mitochondrial voltage-dependent anion channel.
  2. Pharmacological targeting of RIG-I can selectively activate the integrated stress response.
  3. Cytosolic TOP3α facilitates mitochondrial DNA sensing by cGAS.
  4. Cytosine methylase and hydroxymethylase activity in mammalian mitochondria.
  5. A case of POLG-related mitochondrial DNA maintenance defect.
  6. Transcription, Maturation and Degradation of Mitochondrial RNA: Implications for Innate Immune Response.
  7. Site-Specific Mitochondrial RNA N1-Methyladenosine Demethylation via an Engineered MTS-PUF-ALKBH3 Fusion Protein.
  8. Siblings of FBXL4-related mitochondrial DNA depletion syndrome, leading to fatal fulminant pneumonia.
  9. Advancing a sensitive method for measuring mitochondrial ATP production in small muscle biopsy samples.
  10. Super mitochondria-enriched extracellular vesicles enable enhanced mitochondria transfer.
  11. VDAC1 inhibitor DIDS uncouples respiration in isolated tissue mitochondria and induces mitochondrial hyperfusion in mammalian cells.
  12. Advances in the Understanding of Mitochondrial Inflammatory Regulation in the Pathogenesis of Alzheimer's Disease.
  13. A generalized strategy to kill leukemic cells by targeting the regulatory systems governing mitochondrial membrane potential.
  14. VPS35 mutation inhibits PINK1/parkin-mediated mitophagy via increased LRRK2 kinase activity.
  15. A special latch in yeast mitofusin guarantees mitochondrial fusion by stabilizing self-assembly.
  16. Light-evoked activity and BDNF regulate mitochondrial dynamics and mitochondrial localized translation in CNS axons.
  17. Obesity-induced NLRP3 inflammasome activation in nucleus pulposus cells accelerates intervertebral disk degeneration.
  18. High-resolution imaging mass cytometry to map subcellular structures.
  19. Senescent cells promote viral infection-associated inflammation and tissue damage through a robust NF-κB pathway.
  1. Nat Commun. 2025 Oct 27. 16(1): 9481
    Structural basis of apoptosis induction by the mitochondrial voltage-dependent anion channel.
    Melina Daniilidis, Umut Günsel, Georgios Broutzakis, Kira D Leitl, Robert Janowski, Kai Fredriksson, Dierk Niessing, Christos Gatsogiannis, Franz Hagn.
      The voltage-dependent anion channel (VDAC) is the main gateway for metabolites across the mitochondrial outer membrane. VDAC oligomers are connected to apoptosis induced by various stimuli. However, the mechanistic and structural basis of apoptosis induction by VDAC remains poorly understood. Here, using cryo-EM and NMR we show that VDAC1 oligomerization or confinement in small lipid nanodiscs triggers the exposure of its N-terminal α-helix (VDAC1-N) which becomes available for partner protein binding. NMR and X-ray crystallography data show that VDAC1-N forms a complex with the BH3 binding groove of the anti-apoptotic Bcl2 protein BclxL. Biochemical assays demonstrate that VDAC1-N exhibits a pro-apoptotic function by promoting pore formation of the executor Bcl2 protein Bak via neutralization of BclxL. This mechanism is reminiscent of BH3-only sensitizer Bcl2 proteins that are efficient inducers of Bax/Bak-mediated mitochondrial outer membrane permeabilization and ultimately apoptosis. The VDAC pathway most likely responds to mitochondrial stress or damage.
    DOI:  https://doi.org/10.1038/s41467-025-65363-1
  2. Sci Adv. 2025 Oct 31. 11(44): eadt3014
    Pharmacological targeting of RIG-I can selectively activate the integrated stress response.
    Caroline A Cuoco, Wen Ren, Kelsey R Baron, Sakina Gologo, Valerie Perea, Prakhyat Mathur, Prerona Bora, Amina Ta, Alan Chu, Rama Aldakhlallah, Derek Rhoades, Christian M Cole, Ee Phie Tan, William C Hou, Leonard Yoon, Xiaoyan Guo, Jessica D Rosarda, Phil S Baran, Martin Kampmann, Lakeisha Tillery, Kristen A Johnson, Evan T Powers, R Luke Wiseman, Jeffery W Kelly.
      The integrated stress response (ISR) is a eukaryotic stress-responsive signaling pathway that attenuates global protein synthesis while allowing selective translation of specific mRNAs, which together can reestablish homeostasis following acute stress. Diverse pathologic insults activate one or more of the four ISR kinases, which selectively phosphorylate eIF2α to mediate ISR functions. Recent results suggest that enhancing ISR kinase activity could ameliorate pathologies linked to numerous diseases, including many neurodegenerative disorders. However, few pharmacological strategies exist to selectively activate ISR kinases and downstream adaptive signaling. Here, we report that compound A8 can preferentially activate the ISR through the binding of the cytosolic pattern recognition receptor RIG-I, which subsequently activates the heme-regulated inhibitor (HRI) ISR kinase independent of an interferon response. The establishment of A8 and its active metabolite CC81 provides opportunities to probe the biological and therapeutic relationship between innate immune signaling and ISR activation in health and disease.
    DOI:  https://doi.org/10.1126/sciadv.adt3014
  3. EMBO Rep. 2025 Oct 30.
    Cytosolic TOP3α facilitates mitochondrial DNA sensing by cGAS.
    Dongjing Cai, Cheng Chen, Piyanat Meekrathok, Weiqian Zeng, Zheng Wang, Zhigang Peng, Yunan Mo, Xia Xu, Junling Wang, Jian Qiu.
      Mitochondrial DNA (mtDNA) serves as a potent activator for cellular innate immune responses. Topoisomerase 3α (TOP3α), a type IA topoisomerase, is canonically localized to mitochondria and nuclei, but its enigmatic cytosolic fraction-observed over two decades ago-has remained functionally undefined. Here, we uncover a critical role for cytosolic TOP3α in amplifying mtDNA-triggered innate immunity. We observe that aberrant TOP3α expression causes mtDNA clustering and release via mPTP-VDAC, stimulating cGAS-mediated inflammatory responses. Cytosolic TOP3α facilitates the sensing of released mtDNA by cGAS and amplifies downstream innate immune signaling. Using an in vitro cell-free system, we reveal that TOP3α directly augments mtDNA interaction with cGAS, which in turn competes with TOP3α for mtDNA binding. A rare mutation of a highly conserved residue (G250D) of TOP3α impairs the assembly of TOP3α polypeptides into protein complexes and its binding to mtDNA. Furthermore, mutant TOP3α hinders cGAS-mtDNA interaction and compromises cGAS-driven immunity. Our findings reveal a function for cytosolic TOP3α as a regulator for cGAS-driven inflammation.
    Keywords:  Cytosolic TOP3α; Inflammation; Mitochondrial DNA; cGAS
    DOI:  https://doi.org/10.1038/s44319-025-00614-2
  4. Front Cell Dev Biol. 2025 ;13 1677402
    Cytosine methylase and hydroxymethylase activity in mammalian mitochondria.
    Lisa S Shock, Prashant V Thakkar, Jason M Robinson, Shirley M Taylor.
       Introduction: Mitochondria are integral components of eukaryotic cells, functioning as energy powerhouses and key mediators of diverse metabolic and signaling cascades. As endosymbiotic remnants, these unique organelles retain and express their own DNA. Mitochondrial DNA (mtDNA) is packaged into DNA-protein complexes called nucleoids, and is also subject to epigenetic modification. We identified a mitochondrial isoform of DNA methyltransferase 1 (mtDNMT1) that binds to mtDNA in critical control regions; however, its enzymatic activity remained unexplored.
    Results: Here, we show that endogenously-tagged mtDNMT1 purified from mitochondria exhibits time- and concentration-dependent CpG-specific DNA methyltransferase activity, but it is not working alone: DNMT3b cooperates with mtDNMT1 to methylate mtDNA and regulate mitochondrial transcription. In addition, we detect ten-eleven translocase (TET)-like hydroxymethylase activity in mitochondria, demonstrating that mechanisms for both writing and erasing 5-methylcytosine marks are functional in this organelle. CRISPR/Cas9-mediated inactivation of mtDNMT1 and/or DNMT3b activity resulted in a stepwise decrease in mitochondrial methylation across the heavy and light strand promoters of mtDNA, with a significant reduction in transcription of several mtDNA-encoded OXPHOS genes. Interestingly, the effects of mtDNA methylation on mitochondrial transcription are diametrically opposed to the role of promoter methylation in the nucleus, suggesting a novel mode of gene regulation in mitochondria. Cells lacking mtDNMT1 and/or DNMT3b also exhibited a modest reduction in mtDNA content, suggesting that methylation impacts both mtDNA transcription and replication.
    Discussion: These observations implicate mtDNA methylation in the fine-tuning of mitochondrial function and suggest a role for aberrant mitochondrial methylase activity in disease.
    Keywords:  DNA demethylation; DNA methylation; DNA methyltransferase; DNA replication; epigenetics; mitochondrial DNA (mtDNA); transcription
    DOI:  https://doi.org/10.3389/fcell.2025.1677402
  5. Acta Neurol Belg. 2025 Oct 31.
    A case of POLG-related mitochondrial DNA maintenance defect.
    Junyi Wang, Changhong Tan, Fen Deng, Xi Liu, Lifen Chen.
      Mitochondrial DNA (mtDNA) maintenance defects (specifically mtDNA depletion syndromes, MDS) are autosomal recessive disorders caused by a severe reduction in mtDNA content, leading to impaired oxidative phosphorylation and energy deficiency in affected tissues. The clinical heterogeneity of mtDNA maintenance defects correlates with specific gene mutations, with POLG being one of the most frequently implicated genes in mitochondrial dysfunction. We report a novel case of mtDNA maintenance defects manifesting with progressive ocular symptoms, including blepharoptosis, blurred vision, and diplopia, associated with a rare homozygous POLG mutation (c.924G > T, p.Gln308His), which is the second reported homozygous variant at this nucleotide site. Among five previously reported POLG c.924G > T-associated MDS cases, 4 are heterozygous (compound heterozygous or combined with other mitochondrial gene variants). POLG encodes DNA polymerase γ, essential for mtDNA replication; mutations impair mitochondrial function, reducing respiratory chain activity and ATP production. This case adds to the existing literature on the phenotypic variability of POLG-related disorders and expands the known spectrum of pathogenic POLG variants. Despite the rarity of this mutation, its clinical presentation is consistent with classic progressive external ophthalmoplegia (PEO), underscoring the importance of genetic testing in diagnosing mtDNA maintenance defects. Further studies are needed to clarify genotype-phenotype correlations and develop targeted therapeutic strategies for POLG-associated mitochondrial dysfunction.
    Keywords:  DNA polymerase; Mitochondrial DNA (mtDNA) maintenance defects; Progressive external ophthalmoplegia (PEO); The POLG gene
    DOI:  https://doi.org/10.1007/s13760-025-02922-9
  6. Biomolecules. 2025 Sep 28. pii: 1379. [Epub ahead of print]15(10):
    Transcription, Maturation and Degradation of Mitochondrial RNA: Implications for Innate Immune Response.
    Chaojun Yan, Jianglong Yu, Hao Lyu, Shuai Xiao, Dong Guo, Qi Zhang, Rui Zhang, Jingfeng Tang, Zhiyin Song, Cefan Zhou.
      Mitochondria are crucial for a wide range of cellular processes. One of the most important is innate immunity regulation. Apart from functioning as a signaling hub in immune reactions, mitochondrial nucleic acids can themselves act as damage-associated molecular patterns (DAMPs) to participate in immune processes directly. This review synthesizes the current understanding of mitochondrial RNA (mtRNA) biology and its link to immune activation through aberrant accumulation. We focus on its origin through bidirectional mitochondrial transcription and metabolism, encompassing maturation (cleavage, polyadenylation, modification) and degradation. Dysregulation of mtRNA metabolism leads to mt-dsRNA (mitochondrial double-stranded RNA) accumulation, which escapes mitochondria via specific channels into the cytosol and serves as DAMPs to trigger an immune response. We discuss the critical roles of key regulatory factors, including PNPT1 (PNPase, Polyribonucleotide Nucleotidyltrans ferase 1), in controlling mt-dsRNA levels and preventing inappropriate immune activation. Finally, we review the implications of mt-dsRNA-driven inflammation in human diseases, including autoimmune disorders, cellular senescence, and viral infection pathologies, highlighting unresolved questions regarding mt-dsRNA release mechanisms.
    Keywords:  degradation; immune responds; maturation; mitochondrial RNA; transcription
    DOI:  https://doi.org/10.3390/biom15101379
  7. Adv Sci (Weinh). 2025 Oct 27. e10482
    Site-Specific Mitochondrial RNA N1-Methyladenosine Demethylation via an Engineered MTS-PUF-ALKBH3 Fusion Protein.
    Xiangrui Li, Deqiang Kong, Hongmei Liu, Jie Yang, Jiale Zhou, Yuqiang Qian, Ding Zhao, Jinze Li, Xinyu Wu, Tao Zhang, Xiaodi Sun, Yang Han, Liangxue Lai, Zhanjun Li.
      Mitochondrial RNA N1-methyladenosine (m1A) is a prevalent and reversible epitranscriptomic modification. While the biological roles of cytosolic m1A have been increasingly understood, the causal relationship between site-specific mitochondrial m1A and phenotypic outcomes remain elusive, partly due to the lack of precise editing tools. Here, a CRISPR-free mitochondrial RNA m1A demethylation (MRD) editor is reported, which fuses mitochondria-localized engineered PUF RNA-binding protein with the m1A demethylase ALKBH3. Independent cellular assays across multiple sites confirm that MRD editor enables precise demethylation of m1A in mitochondrial mRNAs and tRNAs, leading to correlated changes in mitochondrial protein levels with minimal off-target effects. The MRD editor is further employed to systematically investigate how site-specific mitochondrial m1A alterations regulate cell proliferation, ATP production, mitochondrial membrane potential (MMP), and mitochondrial respiration. Finally, in vivo application of the MRD editor reveals that demethylation of m1A at the A9 position of mitochondrial tRNA-Lys (MT-TK9) induces severe immunodeficiency phenotypes in mice, as evidenced by transcriptomic and histopathological analyses. Collectively, the findings establish MRD as a versatile tool for site-specific mitochondrial RNA m1A editing, offering new insights into the functional dissection of these modifications through chemical biology strategies.
    Keywords:  ALKBH3; Mitochondrial RNA; N1‐methyladenosine; PUF; demethylation editor
    DOI:  https://doi.org/10.1002/advs.202510482
  8. Mol Genet Metab Rep. 2025 Dec;45 101266
    Siblings of FBXL4-related mitochondrial DNA depletion syndrome, leading to fatal fulminant pneumonia.
    Takato Akiba, Shino Shimada, Shimpei Matsuda, Shoji Ishida, Yosuke Baba, Atsushi Yamashita, Hiromichi Shoji, Yasushi Okazaki, Kei Murayama.
      The F-box and leucine-rich repeat protein 4 (FBXL4) is a nuclear encoded mitochondrial protein essential for mitochondrial DNA (mtDNA) maintenance. Biallelic variants in FBXL4 cause FBXL4-related mitochondrial DNA depletion syndrome (FBXL4-MTDPS), characterized by lactic acidosis and developmental delay. We report two siblings diagnosed with FBXL4-MTDPS who died of fulminant pneumonia in infancy; autopsy revealed extensive pulmonary inflammation consistent with severe bacterial infection. FBXL4-MTDPS may involve intrinsic defects in pulmonary infection defense, increasing susceptibility to fatal infection such as pneumonia.
    Keywords:  Encephalomyopathic mitochondrial DNA depletion syndrome; F-box and leucine-rich repeat protein 4; Fatal fulminant pneumonia; Lactic acidosis; Mitophagy
    DOI:  https://doi.org/10.1016/j.ymgmr.2025.101266
  9. Anal Biochem. 2025 Oct 29. pii: S0003-2697(25)00243-X. [Epub ahead of print] 116004
    Advancing a sensitive method for measuring mitochondrial ATP production in small muscle biopsy samples.
    Rolf Wibom, David Alsina, Karin Naess, Martin Engvall, Christoph Freyer, Anna Wedell, Anna Wredenberg.
      We present an optimised luminometric method for measuring muscle mitochondrial ATP production rate (MAPR), adapted to a 96-well microplate format. The enhanced assay enables quantification of ATP production from 12 or more substrate combinations within 15 minutes, using only 10 μL of isolated mitochondria. The method demonstrates high accuracy and precision, with a validated measurement range of 0.3-70 nmol/min/L. To support clinical interpretation, a reference dataset was established from 92 individuals aged seven months to 79 years. All these individuals were referred for muscle biopsy but were subsequently deemed unlikely to have a mitochondrial disorder following comprehensive clinical evaluation. An overview of the current version of our assays for oxidative phosphorylation (OXPHOS) enzymes is also provided. As proof of concept, we present three patients carrying pathogenic variants in mitochondrial DNA (ATP6 and MT-TL1) and the nuclear PDHA1 gene. All exhibited decreased MAPR with one or more substrates, along with additional clinical, biochemical, and morphological features consistent with mitochondrial disease. Furthermore, we illustrate the age-dependent development of MAPR in muscle across the human lifespan, demonstrating a 60-80% higher maximal capacity for oxidative ATP production in adults compared with young children. In contrast, MAPR supported by fatty acid-derived substrates remains unchanged over the same period. In conclusion, the improved MAPR assay offers a robust and efficient tool for assessing mitochondrial function in both clinical diagnostics and research. Its high-throughput format and reliable performance make it particularly well-suited for the investigation of suspected mitochondrial disorders.
    Keywords:  ATP; luciferase; mitochondria; muscle; oxidative phosphorylation; pyruvate
    DOI:  https://doi.org/10.1016/j.ab.2025.116004
  10. Nat Commun. 2025 Oct 27. 16(1): 9448
    Super mitochondria-enriched extracellular vesicles enable enhanced mitochondria transfer.
    Yi Wang, Hao-Yuan Yu, Zi-Juan Yi, Lian-Yu Qi, Jing-Song Yang, Hai-Xin Xie, Min Zhao, Na-Hui Liu, Jia-Qi Chen, Tian-Jiao Zhou, Lei Xing, Xian-Wu Cheng, Hu-Lin Jiang.
      Mitochondria transfer is a spontaneous process that releases functional mitochondria to damaged cells via different mechanisms including extracellular vesicle containing mitochondria (EV-Mito) to restore mitochondrial functions. However, the limited EV-Mito yield makes it challenging to supply a sufficient quantity of functional mitochondria to damaged cells, hindering their application in mitochondrial diseases. Here, we show that the release of EV-Mito from mesenchymal stem cells (MSCs) is regulated by a calcium-dependent mechanism involving CD38 and IP3R signaling (CD38/IP3R/Ca2+ pathway). Activating this pathway through our non-viral gene engineering approach generates super donor MSCs which produce Super-EV-Mito with a threefold increase in yield compared to Ctrl-EV-Mito from normal MSCs. Leber's hereditary optic neuropathy (LHON), a classic mitochondrial disease caused by mtDNA mutations, is used as a proof-of-concept model. Super-EV-Mito rescues mtDNA defects and alleviates LHON-associated symptoms in LHON male mice. This strategy offers a promising avenue for enhancing mitochondria transfer efficiency and advancing its clinical application in mitochondrial disorders.
    DOI:  https://doi.org/10.1038/s41467-025-64486-9
  11. BBA Adv. 2025 ;8 100171
    VDAC1 inhibitor DIDS uncouples respiration in isolated tissue mitochondria and induces mitochondrial hyperfusion in mammalian cells.
    Surajit Das, Arpita Dutta, Minakshi Bedi, Arumay Pal, Shubhra Majumder, Alok Ghosh.
      Mitochondrial outer membrane protein, voltage-dependent anion channel 1 (VDAC1), is a gatekeeper of transport, metabolism, and cellular apoptosis. Ablation of VDAC1 or treatment with small molecular VDAC1 inhibitors often causes metabolic reprogramming in cells. However, the mechanism of VDAC1-mediated reprogramming of mitochondrial oxidative phosphorylation (OXPHOS) is still unclear. To address this problem, we tested how the high-affinity VDAC1 inhibitor, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS), changes cell viability and mitochondrial functions. The IC50 value of DIDS was found 508 µM and 580 µM after 24 h of treatment on human osteosarcoma U2OS and mouse NIH-3T3 fibroblast cells. Moreover, when we inhibited mitochondrial OXPHOS by oligomycin A, 500 µM DIDS was found to uncouple the respiration like the conventional uncoupler CCCP in both the cells. Additionally, we observed that 50-200 µM DIDS, even after 2 h of treatment, depolarizes mitochondrial membrane potential. Also, brief DIDS treatment leads to an increase in cell population with hyperfused mitochondria and attenuation of DRP1 recruitment to mitochondria in U2OS cells. However, no significant alteration in the steady-state level of mitochondrial respiratory chain complex I and complex V subunits was noticed after DIDS treatment. Similar to cell lines, DIDS treatment also showed significant respiratory uncoupling in isolated mitochondria prepared from the normal muscle, liver, and sarcoma tumor tissues of mice. Finally, in silico modeling using AutoDock Vina and AlphaFold3 identified that DIDS binds inside the beta-barrel structure of VDAC1. Together, our findings directly demonstrate that DIDS binds to the VDAC1 inner pocket, uncouples OXPHOS, and promotes mitochondrial hyperfusion.
    Keywords:  DIDS; Mitochondrial dynamics; OXPHOS; Uncoupling; VDAC1; mitochondria
    DOI:  https://doi.org/10.1016/j.bbadva.2025.100171
  12. J Inflamm Res. 2025 ;18 14475-14491
    Advances in the Understanding of Mitochondrial Inflammatory Regulation in the Pathogenesis of Alzheimer's Disease.
    Ren-Zhen Zhang, Li Li, Cui Ma, Ting-Ting Dou, Yu-Ting Wei, Xing-Ke Yan.
      Mitochondria, beyond serving as the powerhouse of the cell, play a pivotal role in the regulation of inflammatory responses. Mitochondrial dysfunction-induced immune activation and chronic inflammation are deeply implicated in the pathogenesis of Alzheimer's disease (AD), influencing its onset and progression through multiple inflammatory pathways. This review summarizes the involvement of several mitochondrial-related mechanisms in AD, including the release of mitochondrial DNA (mtDNA), signal transduction via mitochondrial antiviral-signaling protein (MAVS), the accumulation of mitochondrial damage-associated molecular patterns (DAMPs), the regulation of mitophagy, and the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. These insights aim to shed new light on mitochondrial inflammation as a regulatory mechanism in AD and to explore its potential as a therapeutic target.
    Keywords:  Alzheimer’s disease; inflammatory mechanism; mitochondrion; neuroinflammation; review
    DOI:  https://doi.org/10.2147/JIR.S557000
  13. Cell Rep. 2025 Oct 29. pii: S2211-1247(25)01267-7. [Epub ahead of print]44(11): 116496
    A generalized strategy to kill leukemic cells by targeting the regulatory systems governing mitochondrial membrane potential.
    Ting Liu, Ji-Hao Zhou, Yongbo Gong, Ying Zhang, Yongcan Ma, Xiaowen Zhang, Mohammad Minhajuddin, Wenjie Song, Zixuan Zhuang, Ana Vujovic, Youli Lu, Ang Jia, Rongqun Guo, Ruobing Ren, Lu Zhou, Yu Xiong, Linzhang Huang, Xingrong Du, Tong-Jin Zhao, Peng Li, Craig T Jordan, Haobin Ye.
      Targeting mitochondria emerges as a promising anti-leukemia strategy, yet selective mitochondrial disruption remains challenging. Here, we identified elevated mitochondrial membrane potential (MMP) as a hallmark of leukemic transformation and chemotherapy-resistant cells, prompting screening for MMP-targeting agents. Alexidine (AD), an MMP-depleting compound, demonstrated potent anti-leukemic activity with low toxicity. Mechanistically, AD binds unsaturated cardiolipin to destabilize the inner membrane localization of mitochondrial ribosome, suppressing cardiolipin-dependent mitochondrial translation, a process validated as an independent prognostic marker in leukemia. Interestingly, intercellular heterogeneity in mitochondrial translation drives heterogeneous MMP states within the population, which is associated with stemness and chemoresistance. Intriguingly, this intra-population MMP difference stems not from cardiolipin-mediated translation but from asparagine-driven mitochondrial protein synthesis-a mechanism leukemia cells selectively activate to evade chemotherapy. Critically, pharmacological asparagine depletion synergistically enhances chemosensitivity by disrupting this resistance pathway. Our findings establish that MMP regulation through cardiolipin-maintained homeostasis and asparagine-fueled adaptation represents therapeutic vulnerabilities, advocating co-targeting strategies to overcome resistance.
    Keywords:  CP: cancer; alexidine; asparagine; leukemia stem cells; mitochondrial membrane potential; mitochondrial translation
    DOI:  https://doi.org/10.1016/j.celrep.2025.116496
  14. Brain. 2025 Oct 30. pii: awaf414. [Epub ahead of print]
    VPS35 mutation inhibits PINK1/parkin-mediated mitophagy via increased LRRK2 kinase activity.
    Liselot Manders, Thibaut Heyninck, Dorien Imberechts, Bjørn Holst, Rejko Krüger, Wim Vandenberghe.
      The p.D620N mutation in VPS35 causes an autosomal dominant form of Parkinson's disease via mechanisms that are poorly understood. PINK1 and parkin, two proteins whose loss of function underlies autosomal recessive Parkinson's disease, cooperate to mediate mitophagy, a quality control pathway for selective elimination of damaged mitochondria. PINK1/parkin-mediated mitophagy is disrupted by LRRK2 mutations, which are the most prevalent cause of autosomal dominant Parkinson's disease. Here, we investigated whether the p.D620N VPS35 mutation has an effect on PINK1/parkin-mediated mitophagy. We identified a novel family with autosomal dominant Parkinson's disease caused by a p.D620N VPS35 mutation. We cultured skin fibroblasts and iPSC-derived dopaminergic neurons from the proband and from a second, unrelated Parkinson's disease patient with the p.D620N VPS35 mutation, and compared them with isogenic and non-isogenic control cells. PINK1/parkin-mediated mitophagy was severely impaired in VPS35 mutant fibroblasts and neurons, while non-selective, starvation-induced autophagy and lysosomal degradative capacity were preserved. siRNA-mediated VPS35 knockdown rescued the mitophagy defect in VPS35 mutant cells, whereas overexpression of wild-type VPS35 did not, suggesting a gain-of-function mechanism of the mutation. The VPS35 mutation did not interfere with activation of PINK1 or parkin after mitochondrial depolarization, but impaired mitochondrial recruitment of the autophagy receptor optineurin. LRRK2 kinase activity was increased in the VPS35 mutant cells, as shown by enhanced levels of the T73-phosphorylated form of the LRRK2 substrate RAB10. The enhanced level of phosphorylated RAB10 in VPS35 mutant cells was decreased by treatment with LRRK2 kinase inhibitors and by VPS35 knockdown. Importantly, the mitophagy defect of VPS35 mutant fibroblasts and neurons was fully rescued by LRRK2 kinase inhibitors as well as by overexpression of PPM1H, a phosphatase that dephosphorylates multiple RAB substrates of LRRK2. Finally, in situ proximity ligation experiments revealed that endogenous VPS35 and LRRK2 are proximity partners in human dopaminergic neurons and that this proximity relationship is enhanced by the VPS35 mutation. In conclusion, the VPS35 mutation impairs PINK1/parkin-mediated mitophagy via a gain-of-function mechanism that involves stimulation of LRRK2 kinase activity. Thus, a VPS35/LRRK2 axis linked to dominant Parkinson's disease intersects with a pathway mediated by proteins encoded by the recessive Parkinson's disease genes.
    Keywords:  Parkinson’s disease; RAB; autophagy; induced pluripotent stem cell; lysosome; mitochondrion
    DOI:  https://doi.org/10.1093/brain/awaf414
  15. Nat Commun. 2025 Oct 31. 16(1): 9644
    A special latch in yeast mitofusin guarantees mitochondrial fusion by stabilizing self-assembly.
    Shu-Jing Huang, Dong-Fei Ma, Caiting Yu, Jing Li, Xinyu Tu, Zi Huang, Yuanbo Qi, Jun-Ying Ou, Jian-Xiong Feng, Bing Yu, Yu-Lu Cao, Jia-Xing Yue, Junjie Hu, Ming Li, Ying Lu, Liming Yan, Song Gao.
      The mitochondrion is a highly dynamic organelle, constantly undergoing fusion and fission, which are critical processes for the health of cells. Fusion of the outer mitochondrial membrane (OMM) is mediated by the mitofusins belonging to the dynamin superfamily of GTPases. Most eukaryotic organisms possess two cooperatively functioning mitofusins, but yeast has only one mitofusin (Fzo1). How Fzo1 solely catalyzes OMM fusion is unclear. Here, we present crystal structures of truncated Fzo1 (Fzo1IM) in different nucleotide-loading states and report a special mechanistic feature of Fzo1 through systematic functional studies. Differing from mammalian mitofusins, Fzo1 contains an extra latch bulge (LB) that is essential for the viability of yeast. Upon GTP loading, Fzo1IM dimerizes via the GTPase domain and prefers the closed conformation. This state is then locked by the subsequent trans interaction mediated by the LB of each protomer, so that Fzo1IM remains dimerized in the closed conformation even after GTP hydrolysis. This special mechanistic feature may be relevant to the previous observation that degradation of Fzo1 by the ubiquitin-proteasome system is required for mitochondrial fusion. Our study reveals how mitochondrial fusion in yeast is efficiently ensured with limited GTP consumption, which broadens current understanding of this fundamental biological process.
    DOI:  https://doi.org/10.1038/s41467-025-64646-x
  16. iScience. 2025 Oct 17. 28(10): 113563
    Light-evoked activity and BDNF regulate mitochondrial dynamics and mitochondrial localized translation in CNS axons.
    Alexander Kreymerman, Jessica E Weinstein, Nirmal Vadgama, Sahil H Shah, Michael M Nahmou, Kinsley C Belle, Marco H Ji, Xin Xia, Anne Faust, Yolandi Van Der Merwe, David N Buickians, In-Jae Cho, Star K Huynh, Sonya Verma, Kristina Russano, Xiao-Lu Jin, Ioannis Karakikes, Michael B Steketee, Jeffrey L Goldberg.
      Mitochondria coordinate well-described maintenance functions within neuronal axons and dendrites. However, less is known about how mitochondria are regulated during axon development and maturation. Here, we demonstrate that within the developing visual system, retinal ganglion cell (RGC) axons in the retina and optic nerve exhibit increases in mitochondria size, number, and total area in vivo. Our findings indicate that these developmental changes in mitochondria are driven by neuronal activity associated with eye opening and by brain-derived neurotrophic factor (BDNF). These events occur in concert with downstream gene and protein expression changes consistent with mitochondrial biogenesis and energetics pathways. We further demonstrate that activity- and BDNF-regulated transcripts are localized and translated at mitochondria within RGC axons in vivo, concomitant with the regulation of mitochondrial dynamics. These data highlight the previously undescribed regulation of mitochondrial dynamics in axonal maturation, dependent on mechanisms involving neuronal activity and neurotrophic factor signaling, coordinated with mitochondrial-localized translation.
    Keywords:  Biological sciences; Natural sciences; Neuroscience; Systems neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2025.113563
  17. J Orthop Surg Res. 2025 Oct 29. 20(1): 934
    Obesity-induced NLRP3 inflammasome activation in nucleus pulposus cells accelerates intervertebral disk degeneration.
    Shuai Gao, Na-Na Su, Qiang Zhao, Fang-Fang Wang, Shuan-Chi Wang, Wei Guo.
      Intervertebral disc degeneration (IVDD) is a common imaging change, and it is characterized by increased production of inflammatory cytokines such as IL-1β and elevated degradation of extracellular matrix (ECM). IVDD has been indicated as the most important reason of low back pain and the leading cause of disability. IVDD is a common concomitant disease in patients with obesity; and obesity is a metabolic syndrome pathological condition that results in the concentrations of circulating fatty acid increasing and metabolic stress. Increasing circulating fatty acid could evoke a widespread inflammation response, leading to ECM degradation. Yet, how IVDD is induced by obesity, and how circulating fatty acid affects nucleus pulposus cells inflammatory response is unclear. Here we present evidence that a high fat diet (HFD) leads to IVDD and saturated fatty acid induces the activation of NLRP3 inflammasome, causing caspase-1, IL-1β production and HMGB1 release in NP cells. This involves mitochondria dsRNA (mt-dsRNA) release and double-stranded RNA-dependent protein kinase (PKR) activation. PKR deficiency inhibited NLRP3 inflammasome activation and catabolic degeneration in NP cells and rescued the phenotypes of IVDD in vivo and in vitro. Moreover, metformin prevents PKR activation and protects NP cells by attenuating mitochondria damage to NP cells. This research presents a comprehensive understanding of NLRP3 inflammasome activation mediated by mt-dsRNA-PKR axis in NP cells that underlies the development of IVDD and recommends metformin as a therapeutic drug for treating IVDD.
    Keywords:  Intervertebral disc degeneration; Mitochondrial DsRNA; Obesity; PKR; Pyroptosis
    DOI:  https://doi.org/10.1186/s13018-025-06382-y
  18. Nat Methods. 2025 Oct 30.
    High-resolution imaging mass cytometry to map subcellular structures.
    Alina Bollhagen, James Whipman, Ricardo Coelho, Viola Heinzelmann-Schwarz, Francis Jacob, Bernd Bodenmiller.
      Imaging mass cytometry (IMC) is a powerful multiplexed imaging technology used to investigate cell phenotypes and spatial organization of tissue in health and disease. The spatial resolution of IMC is presently at 1 µm, enabling the resolution of single cells and large subcellular compartments but not submicrometer intracellular structures. Here we report a method to improve the resolution of IMC so that it approaches that of light microscopy. High-resolution IMC (HR-IMC) uses an oversampling approach coupled with point-spread function-based deconvolution to achieve a resolution below 350 nm. We demonstrate the performance of HR-IMC in resolving subcellular structures, such as nuclear foci and mitochondrial networks previously undetectable with IMC, and applied it to visualize chemotherapy-induced perturbation of patient-derived ovarian cancer cells. HR-IMC extends highly multiplex IMC analyses into the subcellular regime, enabling analysis of cell biological features and characteristics of disease.
    DOI:  https://doi.org/10.1038/s41592-025-02889-8
  19. Cell Commun Signal. 2025 Oct 28. 23(1): 464
    Senescent cells promote viral infection-associated inflammation and tissue damage through a robust NF-κB pathway.
    Mingfu Tian, June Ma, Zhiqiang Li, Chenglin Ye, Xianghua Cui, Guolei Wang, Siyu Liu, Muhammad Suhaib Qudus, Uzair Afaq, Hong Fan, Jiali Xiong, Guangli Li, Chuanjin Luo, Zhen Wang, Zhengjiang Jin, Ming Guo, Xin Wang, Zhixiang Huang, Fang Zheng, Kailang Wu, Chengliang Zhu.
      Respiratory virus infections have been presenting significant global public health challenges. The virulence of SARS-CoV-2 and seasonal influenza largely relies on triggering abnormal host immune responses, particularly the production of a cytokine storm, which is notably increased in elderly patients. However, as the mechanisms underlying this age-associated exacerbation remain unclear, we investigated the role of the aging tissue microenvironment in promoting inflammation associated with viral infection. Our research, based on clinical samples, cellular experiments, and mouse models, provides evidence that the aging lung microenvironment induces severe inflammatory responses and leads to tissue damage, with senescent cells playing a crucial role in this process. Further mechanistic insights reveal that elevated levels of downstream inflammatory factors result from a significant and robust activation of the NF-κB pathway. This increase is attributed to the accumulation of reactive oxygen species in senescent cells and subsequent reduced expression of PDLIM2, an E3 ubiquitin ligase regulating P65 degradation. Finally, restoring PDLIM2 significantly inhibits viral infection-mediated inflammatory responses and organ damage in the aging body. Therefore, this study offers a novel perspective by elucidating the molecular mechanism and exploring the therapeutic potential behind viral infection-related inflammatory responses, particularly the mechanism accelerating inflammatory storms in elderly patients post-infection.
    Keywords:  Inflammation; NF-κB; PDLIM2; Senescence; Virus
    DOI:  https://doi.org/10.1186/s12964-025-02466-8
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